piperidines and carbizocaine

The aim of this review is to describe the pharmacology, toxicology and chemistry of the new group of local anesthetics of phenylcarbamic acid type.. Basic esters of alkoxy-substituted phenylcarbamic acid have shown high local anesthetic potency, while maintaining a relatively safe toxicity profile. Their potency uniquely increases with the decreasing pH of the external medium. This is of importance when using local anesthesics in inflamed tissues, where the action of common local anesthetics is often problematic.. The most potent phenylcarbamic anesthetics exceed the potency of the most common clinically used local anesthetics 100-300 times. Due to the unique pH dependency of these local anesthetics, further study of their action is required.

Topics: Amides; Anesthetics, Local; Animals; Carbamates; Dose-Response Relationship, Drug; Esters; Humans; Hydrogen-Ion Concentration; Lethal Dose 50; Molecular Structure; Phenylcarbamates; Piperidines; Sciatic Nerve; Structure-Activity Relationship

The paper studies the kinetics of alkaline hydrolysis and stability under non-isothermal conditions of heptacainium chloride and carbisocainium chloride in the medium of aqueous-ethanolic solution of sodium hydroxide c = 0.1 mol/l and buffer solutions of values of pH 7.0 and pH 8.0. The results of the study of the kinetics of hydrolysis by means of a non-isothermal test - rate constants and activation energy values served as the basis for exact evaluation of the stability of these potential pharmaceuticals. The objective of the paper links up with the previous studies of these substances.

Topics: Anesthetics, Local; Carbamates; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Piperidines; Sodium Hydroxide; Solutions; Water

Effects of local anesthetics heptacaine and carbisocaine on mouse peritoneal macrophages after 5 days of peritoneal administration were observed. Both compounds in a daily dose 50 mg/kg caused significant decrease in phagocytic activity and index of phagocytosis (number of ingested particles). No significant effects on phagocytosis were observed when carbisocaine was administrated in a daily dose 5 mg/kg. No significant changes in weight gain and number of peritoneal macrophages were observed in all groups.

Topics: Anesthetics, Local; Animals; Body Weight; Carbamates; Female; Leukocyte Count; Liver; Macrophages; Mice; Mice, Inbred C57BL; Organ Size; Phagocytosis; Piperidines; Spleen

The present study aimed to find a suitable HPLC system for the determination of the values of the capacity factor of k' pentacaine, carbisocaine, heptacaine, and its 3-, and 4-positional isomers. The column Separon SG X C-18 and a mobile phase consisting of 90% methanol and 10% water (with 0.5 mol/l of sodium acetate) were demonstrated to be suitable for the separation of these potential local anaesthetics from the group of phenylcarbamic acid derivatives. In this system, k'o for pentacaine is 22.9, for carbisocaine 8.6, for heptacaine 8.1, and for 3-positional derivative of heptacaine, 13.0, and 4-isomer, 18.4. It results from the data that log k' of these drugs is in the interval 2-5 and even minor changes in the concentration of sodium acetate (c = 0.5 +/- 0.05 mol/l) do not change it markedly.

Topics: Anesthetics, Local; Carbamates; Chromatography, High Pressure Liquid; Isomerism; Piperidines

A HPLC method is described for the simultaneous determination of the phanylcarbamate type anesthetics heptacaine and carbisocaine and their metabolites. Using this method the in vitro degradation of these drugs in urine, human and rabbit serums was investigated. The slower degradation of carbisocaine was explained on the basis of steric hindrance.

Topics: Anesthetics, Local; Animals; Biodegradation, Environmental; Carbamates; Chromatography, High Pressure Liquid; Humans; Indicators and Reagents; Piperidines; Rabbits

The inhibitory effects of the prospective antiarrhythmic drug BK 129 on Ca2+ and Na+ inward currents (ICa and INa, respectively) and on fast inactivating and slow noninactivating K+ outward currents (IKf, IKs, respectively) were tested in young rat sensory neurons by modified whole cell voltage clamp technique in vitro. The effects were compared to those of nifedipine, verapamil and local anesthetic carbisocaine. Both BK 129 and carbisocaine are basic carbanilates. At a frequency of test pulses of 0.2 Hz apparent dissociation constants (pD2) of BK 129 to channels conducting ICa, INa, IKf, and IKs were 5.313, 4.429, 3.985, and 4.154, of carbisocaine 5.428, 5.896, 3.992, and 4.091, and of verapamil 4.249, 4.093, 3.839, and 4.453, respectively. In nifedipine only the pD2 for ICa inhibition could be measured (5.624). This drug failed to exert any appreciable effect on the other currents up to the highest concentration used (15 mumol/l). Higher concentrations could not be tested because of the interfering effect of nifedipine solubilizer (ethanol). The inhibiting effect of verapamil on ICa revealed slight potential dependence which however, could not account for the observed low specificity of this drug. Frequency of calcium channel activations might be more important determinant of the verapamil induced ICa inhibition rather than the holding potential. The weak inhibiting effect of omega-conotoxin GVIA (5 mumol/l) and Ni2+ (100 mumol/l) as well as the strong effect of Cd2+, Co2+ (both 5 mmol/l) and nifedipine on ICa indicated that it was mainly the L type Ca2+ channel that conducted this current. The differential effect of Cd2+ and Co2+ (5 mmol/l) compared to tetrodotoxin (3 mumol/l) on ICa and INa disproved the possibility that these currents would pass via identical channels. While nifedipine was shown to be a highly specific inhibitor of ICa in the young rat sensory neurons the other drugs tested inhibited the currents with a much smaller selectivity, with verapamil being the least specific at low stimulus rates (0.2 Hz). BK 129 is a powerful although nonspecific blocker of the inward ICa in the neuronal membrane. It is suggested that these properties of BK 129 might participate in its antiarrhythmic effect.

Topics: Animals; Anti-Arrhythmia Agents; Azepines; Calcium Channel Blockers; Carbamates; Ganglia, Spinal; Membrane Potentials; Neurons, Afferent; Nifedipine; Piperidines; Rats; Verapamil

The potential mutagenic activity of three carbamate derivatives with local anaesthetic activity was investigated. Genotoxic activity was observed after application of Carbisocaine on Euglena gracilis, whereas no activity was detected by Carbisocaine, Heptacaine and Pentacaine on Salmonella typhimurium, Escherichia coli and Drosophila melanogaster.

Topics: Anesthetics, Local; Animals; Carbamates; DNA Repair; Drosophila melanogaster; Escherichia coli; Euglena; Genes, Lethal; Genes, Recessive; Mutagenicity Tests; Mutagens; Piperidines; Salmonella typhimurium

The passage of 6 model drugs; acetylsalicylic acid, chloramphenicol, ethimizol, carbisocaine, heptacaine, and diazepam, through the blood-brain barrier, was determined in unirradiated control rats and in animals 1, 3, and 7 days after irradiation of the head only with a dose of 25 Gy from a 60Co source. The brain uptake index (BUI), which compares the uptake of the test substance with that of 3H2O 5 s after their injection into the common carotid artery, was significantly increased in comparison with unirradiated controls 7 days after irradiation, for all substances tested except for ethimizol. For acetylsalicylic acid and chloramphenicol it was also significantly increased in the other time intervals. The less lipophilic substances showed a greater relative increase of BUI than the more lipophilic ones.

Topics: Animals; Aspirin; Blood-Brain Barrier; Brain; Carbamates; Chloramphenicol; Cobalt Radioisotopes; Cranial Irradiation; Diazepam; Etimizol; Male; Piperidines; Rats; Rats, Inbred Strains; Regression Analysis

Topics: Carbamates; Chemical Phenomena; Chemistry; Drug Stability; Hydrogen-Ion Concentration; Piperidines; Temperature; Time Factors; Ultraviolet Rays

Electrophysiological investigations of new drugs with carbanilate structure (heptacaine, carbisocaine) on axons and sciatic nerves of the rat have shown their high local anaesthetic effect at physiological pH. This effect is not only maintained at acid pH (6.0); it even increases on shifting pH from basic to acid values. To study this unique pH dependence of the effect of new local anaesthetics, drug-lipid interactions were investigated in liposomes prepared from egg yolk phosphatidylcholine or dimyristoyl phosphatidylcholine. The effect of the local anaesthetics on the molecular ordering of lipids in the liposomes was measured from spectral anisotropy of spin-labelled fatty acid incorporated in the membrane. It was concluded that the change of pH from 9.5 to 6.5 not only sustains the disordering effect of heptacaine and carbisocaine; it even potentiates it with the maximum disordering effect recorded at pH 6.5. This trend towards pH dependence in the effect of the new local anaesthetics is similar to that observed in biological preparations and is quite unlike the case of classic local anaesthetics (procaine, lidocaine). The possible mechanism of pH dependence is discussed.

Topics: Anesthetics, Local; Carbamates; Chemical Phenomena; Chemistry, Physical; Electron Spin Resonance Spectroscopy; Hydrogen-Ion Concentration; Membranes, Artificial; Models, Chemical; Piperidines; Spin Labels

Topics: Anesthetics, Local; Animals; Blood Platelets; Carbamates; Histamine Release; In Vitro Techniques; Male; Mast Cells; Piperidines; Rats; Rats, Inbred Strains; Serotonin

In the present study effects of a new local anaesthetics, pentacaine (trans-2-pyrolidinocyclohexylester of 3-pentyloxyphenylcarbamic acid), and of some chemically related compounds on rat hepatic adenylate cyclase activity were studied under various experimental conditions. As compared with tetracaine, the local anaesthetics tested showed stronger inhibitory effects, regardless of the type of stimulating agents used to activate adenylate cyclase. The most potent effect was observed with pentacaine. Its inhibitory effects on glucagon, guanylylimidodiphosphate (Gpp/NH/p), sodium fluoride or forskolin stimulated activity suggest that it may directly act on the catalytic unit of adenylate cyclase. The same conclusion can be drawn based on its inhibitory effects on adenylate cyclase, regardless ATP concentrations used as the enzyme substrate, and on octylpyranoside solubilized enzyme activated by preincubation of the enzyme preparation with Gpp/NH/p. Structure-activity studies have suggested that the pentacaine molecule as a whole and none of its parts alone or its analogs are responsible for the inhibitory effect. However, the inhibitory effects of these compounds on the rat adenylate cyclase activity do not correlate with their local anaesthetic properties. The possibility of using adenylate cyclase inhibitors to decrease cyclic AMP production under pathological conditions, like in cholera, known to be due to a high adenylate cyclase activity, is discussed.

Topics: Adenylyl Cyclase Inhibitors; Anesthetics, Local; Animals; Carbamates; Colforsin; Glucagon; Glucosides; Guanylyl Imidodiphosphate; Liver; Piperidines; Rats; Structure-Activity Relationship